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Chapter 33 : Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”

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Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, Page 1 of 2

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Abstract:

Antibiotics are synthesized by dedicated gene products; they are anything but accidents. All the structural genes required for tylosin biosynthesis are probably present in the cluster, but additional regulatory genes might well be located elsewhere in the genome. Antibiotic-biosynthetic gene clusters commonly include ‘‘pathway-specific’’ regulators. These typically encode transcriptional activators that turn on the structural genes for antibiotic production. Antibiotic-producing organisms are typically resistant to their own toxic metabolite(s), and some of the strategies employed for self-protection are discussed below and elsewhere. Such resistance is usually quite specific for the avoidance of suicide; across-the-board resistance is not common. The fungus that produces penicillin is not faced with any particular problem as a result of doing so, since fungal cell walls do not contain peptidoglycan. On the other hand, actinomycetes that produce antibacterial compounds pose an interesting challenge for themselves. Such strains can adopt either of two resistance strategies in order to avoid suicide. Studies with puromycin and chloramphenicol revealed that peptidyltransferase activity has to do with the larger ribosomal subunit, whereas tetracycline blocked aminoacyl-tRNA binding to the ribosome mRNA complex from a site on the smaller subparticle. The convergence of these various approaches will reveal in molecular detail how antibiotics block conformational transitions that underlie ribosomal function. The ribosome continues to be a focus for the application of ground-breaking methodology to biological systems, and enigmatic small molecules still contribute to our enlightenment.

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33

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Figures

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Figure 1

Structures of tylactone and tylosin.

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
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Image of Figure 2
Figure 2

Tylosin-biosynthetic gene cluster of (not drawn to scale). The total size of the cluster is ~85 kb, of which the five genes occupy ˜41 kb. The data are taken from ; and . The genes were sequenced at Lilly Research Laboratories (Indianapolis, Ind.) (GenBank accession no. U78289) but not formally published. Data relating to open reading frames 8 to 10 also originated at Lilly (DeHoff and Rosteck, personal communication).

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
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Figure 3

Biosynthesis of the tylosin sugars. During assembly of the tylosin molecule, mycaminose is the first sugar added to the polyketide ring, followed, in a preferred but not obligatory order, by deoxyallose and mycarose. After addition to the ring, the deoxyallose moiety is converted to mycinose via bis Omethylation, involving sequential action of the and products.

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
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Image of Figure 4
Figure 4

Structure of the γ-butyrolactone signal molecule, Afactor.

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
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References

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Tables

Generic image for table
Table 1

Antibiotic-inactivating enzymes in organisms producing ribosome inhibitors

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
Generic image for table
Table 2

Resistance due to methylation of rRNA in antibiotic producers

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33
Generic image for table
Table 3

Antibiotic resistance due to altered properties of nonribosomal drug targets

Citation: Cundliffe E. 2000. Antibiotic Biosynthesis: Some Thoughts on “Why?” and “How?”, p 409-418. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch33

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